5N13

Second Bromodomain (BD2) from Candida albicans Bdf1 in the unbound form

5N13 の概要

• エントリーDOI: 10.2210/pdb5n13/pdb
• 分子名称: Bromodomain-containing factor 1, GLYCEROL (3 entities in total)
• 機能のキーワード: bromodomain, transcription
• 由来する生物種: Candida albicans (Yeast)
• 細胞内の位置: Nucleus : Q5A4W8
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12810.52

構造登録者

Mietton, F.,Ferri, E.,Champlebouxm, M.,Zala, N.,Maubon, D.,Zhou, Y.,Harbut, M.,Spittler, D.,Garnaud, C.,Courcon, M.,Chauvel, M.,d'Enfert, C.,Kashemirov, B.A.,Hull, M.,Cornet, M.,McKenna, C.E.,Govin, J.,Petosa, C. (登録日: 2017-02-04, 公開日: 2017-05-31, 最終更新日: 2024-01-17)

主引用文献

Mietton, F.,Ferri, E.,Champleboux, M.,Zala, N.,Maubon, D.,Zhou, Y.,Harbut, M.,Spittler, D.,Garnaud, C.,Courcon, M.,Chauvel, M.,d'Enfert, C.,Kashemirov, B.A.,Hull, M.,Cornet, M.,McKenna, C.E.,Govin, J.,Petosa, C.
Selective BET bromodomain inhibition as an antifungal therapeutic strategy.
Nat Commun, 8:15482-15482, 2017

PubMed Abstract: Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.

PubMed: 28516956
DOI: 10.1038/ncomms15482

実験手法

X-RAY DIFFRACTION (1.2 Å)